Most cancer patients treated with molecular-directed therapies have short-lived or incomplete responses. While responses to novel immunotherapies breaking tolerance to tumor antigens are promising, only a minority of patients respond to this therapies. Therefore, combination therapies will be required, both among targeted small molecules and between immunotherapies and small molecule inhibitors, but it is not clear how to prioritize testing these combinations, particularly as some targeted inhibitors can antagonize immune system effector functions. Established cancer cell lines are known to be limited in their ability to predict patient responses and cannot on their own model non- autonomous interactions with the immune system. We have validated an ex vivo culture system of patient tumors within days from biopsy that captures functional information complimentary to molecular analysis. Importantly, this system evaluates non- autonomous effects in both tumor and stromal populations, including tumor-infiltrating lymphocytes (TILs). Here, we propose use this technology to discover novel combinations of targeted agents for melanoma therapy in patient samples and to model interactions between small molecules and immunotherapy on tumor cell antigen expression and TIL effector functions. Lastly, we will explore the clinical validity of thi technology as a diagnostic assay to predict response of BRAF-mutant melanoma to BRAF inhibitors. Therefore, we propose the following specific aims: